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Using mice to model neural responses, scientists have identified bullying
and
other social stress symptoms triggered by depression,
to be activated by GABA neurons.Above, mouse neurons (green) are inhibited by the release of serotonin (red).
The scientists were able to "switch off" these neurons which made the mice resilient to bullying.

Findings point to new potential drug target—GABA neurons—to treat patients with depression and other mood disorders.

A new drug target to treat mood disorders such as depression, may lie in a group of GABA neurons (gamma-aminobutyric acid, the neurotransmitters which inhibit other cells) shown to contribute to symptoms like social withdrawal and increased anxiety, Penn Medicine researchers report in a new study in the Journal of Neuroscience.

Experts know that people suffering from depression and other mood disorders often react to rejection or bullying by withdrawing themselves socially more than the average person who takes it in strides, yet the biological processes behind these responses have remained unclear.

Using a mouse model, scientists identified bullying and other social stress symptoms triggered by depression, were activated by GABA neurons. A direct relationship between social stimuli and this neural circuitry comes from the lab of Olivier Berton, PhD, assistant professor, department of Psychiatry, collaboratng with Sheryl Beck, PhD, professor, department of Anesthesiology, both at the Children's Hospital of Philadelphia.

Conversely, when the researchers successfully 'quieted' the effect of GABA neurons, mice became more resilient to bullying and didn't avoid previously perceived threats.

"This is the first time that GABA neuron activity—found deep in the brainstem—has been shown to play a key role in the cognitive processes associated with social approach or avoidance behavior in mammals.

"The results help us to understand why current antidepressants may not work for everyone and how to make them work better—by targeting GABA neurons that put the brake on serotonin cells."

Reduced serotonin production elicits socially defensive responses such as avoidance and/or submission, where as enhancing serotonin production—the intended goal of antidepressants—induces a positive perception of social effectiveness, promoting affiliation and dominance.

By comparing gene expression in the brains of resilient and avoidant mice, Berton and colleagues discovered that bullying in avoidant mice puts GABA neurons in an 'excited' state with mice exhibiting signs of social defeat. Resilient mice, however, had no change in neuron levels or behavior.

Current antidepressants targeting serotonin, such as SSRIs, are only effective in about 50 percent of patients. With the current findings, new treatments for SSRI non-responsive patients may be able to be developed.

To better understand the link between GABA and the development of stress resilience, Berton and colleagues devised an optogenetics-based approach to directly manipulate serotonin levels:

lifting GABA inhibition of serotonin neurons reduced social and anxiety symptoms in mice exposed to bullies and fully prevented neurobiological changes due to stress.

"Our paper provides a novel cellular understanding of how social defensiveness and social withdrawal develop in mice and gives us a stepping stone to better understand the basis of similar social symptoms in humans," said Berton. "This has important implications for the understanding and treatment of mood disorders."

Abstract
Serotonin (5-HT) modulates neural responses to socioaffective cues and can bias approach or avoidance behavioral decisions, yet the cellular mechanisms underlying its contribution to the regulation of social experiences remain poorly understood. We hypothesized that GABAergic neurons in the dorsal raphe nucleus (DRN) may participate in socioaffective regulation by controlling serotonergic tone during social interaction. We tested this hypothesis using whole-cell recording techniques in genetically identified DRN GABA and 5-HT neurons in mice exposed to social defeat, a model that induces long-lasting avoidance behaviors in a subset of mice responsive to serotonergic antidepressants. Our results revealed that social defeat engaged DRN GABA neurons and drove GABAergic sensitization that strengthened inhibition of 5-HT neurons in mice that were susceptible, but not resilient to social defeat. Furthermore, optogenetic silencing of DRN GABA neurons disinhibited neighboring 5-HT neurons and prevented the acquisition of social avoidance in mice exposed to a social threat, but did not affect a previously acquired avoidance phenotype. We provide the first characterization of GABA neurons in the DRN that monosynaptically inhibit 5-HT neurons and reveal their key role in neuroplastic processes underlying the development of social avoidance.

This work was funded by the National Institute of Mental Health grants MH087581, MH0754047 and MH089800 and grants from the International Mental Health Research Organization, the National Alliance for Research on Schizophrenia and Depression and the National Institute on Drug Abuse.